The nonthyroidal illness syndrome (NTIS), also called the sick euthyroid syndrome, is the state of a low serum thyroid hormone (T3) concentration associated with any acute or chronic illness, without intrinsic disease of the hypothalamic-pituitary-thyroid axis. The severity of the NTIS correlates directly with the severity of illness, and multiple studies show that the severity of the NTIS is an independent and powerful predictor of mortality. The long term objectives of these studies are to understand the mechanisms underlying the NTIS and to address whether it should ever be treated, and if so, what the treatment should be. The first Specific Aim will use cell culture and in vivo mouse models to address the mechanisms underlying the decreased conversion of thyroxine to T3 that characterizes the NTIS. The activity and expression of type 1 iodothyronine deiodinase (D1) are known to be decreased by illness. This effect is due at least in part to a defective ability of thyroid hormone receptors to induce transcription of the D1 gene, Dio1. The relationship between defective D1 expression, the low serum T3, and thyroid hormone receptor coactivator function will be investigated. Specific Aim 2 will use two in vivo mouse models of NTIS, endotoxin administration and sepsis, to test whether a specific therapy (forced expression of a thyroid hormone receptor coactivator) can ameliorate the NTIS and decrease mortality rate. Specific Aim 3 will evaluate the basis for impaired thyroid hormone receptor coactivator function in the NTIS. Cytokine or illness-associated potential mechanisms to be explored include induction of corepressors that compete with the coactivators, redistribution of coactivators to other genes, redistribution of coactivators to other regions of the cell, and abnormalities in post-translational modifications of coactivators. The severity of the nonthyroidal illness syndrome (NTIS) correlates directly with the severity of illness, and multiple studies show that the severity of the NTIS is an independent and powerful predictor of mortality. These studies will address whether treatment of the NTIS improves recovery from serious medical illnesses.